Dosage & Administration
For autologous use only. For intravenous use only.
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Kymriah Prescribing Information
- Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.3, 2.4), Warnings and Precautions (5.1)].
- Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed [see Warnings and Precautions (5.2)].
- T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19- directed genetically modified autologous T cell immunotherapies, including KYMRIAH [see Warnings and Precautions (5.9)].
- KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS [see Warnings and Precautions (5.3)].
KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia
Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma
Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.
Adult Relapsed or Refractory Follicular Lymphoma
Adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy.
This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
For autologous use only. For intravenous use only.
Dosage in Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia
KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells.
Based on the patient weight reported at the time of leukapheresis:
- Patients 50 kg or less: administer 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight.
- Patients above 50 kg: administer 0.1 to 2.5 x 108 CAR-positive viable T cells.
Dosage in Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma
KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells.
- For adult patients: administer 0.6 to 6.0 x 108 CAR-positive viable T cells.
Administration
Preparing Patient for KYMRIAH Administration with Lymphodepletion
- Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen.
Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia
- Lymphodepleting chemotherapy: Fludarabine (30 mg/m2 intravenously daily for 4 days) and cyclophosphamide (500 mg/m2 intravenously daily for 2 days starting with the first dose of fludarabine).
- Infuse KYMRIAH 2 to 14 days after completion of the lymphodepleting chemotherapy.
Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and r/r Follicular Lymphoma
• Lymphodepleting chemotherapy: Fludarabine (25 mg/m2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine).
• Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 intravenously daily for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen.
• Infuse KYMRIAH 2 to 11 days (r/r DLBCL) or 2 to 6 days (r/r FL) after completion of the lymphodepleting chemotherapy.
• Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count is less than 1 x 109/L within 1 week prior to KYMRIAH infusion.
Preparation of KYMRIAH for Infusion and Administration
Delay the infusion of KYMRIAH if a patient has unresolved serious adverse reactions (including pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy [see Warnings and Precautions (5.1)].
A KYMRIAH dose may be contained in one to three cryopreserved patient specific infusion bag(s). Verify the number of bags received for the dose of KYMRIAH with the Certificate of Conformance (CoC) and Certificate of Analysis (CoA). Coordinate the timing of thaw of KYMRIAH and infusion in the following manner. Confirm the infusion time in advance, and adjust the start time for thaw so that KYMRIAH is available for infusion when the recipient is ready. If more than one bag has been received for the treatment dose, thaw 1 bag at a time. Wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered.
Preparation of KYMRIAH for Infusion
1. Ensure tocilizumab and emergency equipment are available prior to infusion and during the recovery period.
2. Premedicate patient with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to KYMRIAH infusion. Avoid prophylactic use of systemic corticosteroids, as it may interfere with the activity of KYMRIAH.
3. Confirm patient identity: Prior to KYMRIAH preparation, match the patient's identity with the patient identifiers on each KYMRIAH infusion bag(s). KYMRIAH is for autologous use only. Employ universal precautions to avoid potential transmission of infectious diseases when handling the product.
Note: The patient identifier number may be preceded by the letters DIN or Aph ID.
Figure 1. KYMRIAH Infusion Bag
4. Inspect the infusion bag(s) for any breaks or cracks prior to thawing. If a bag is compromised, do not infuse the contents. Call Novartis at 1-844-4KYMRIAH.
5. Place the infusion bag inside a second, sterile bag in case of a leak and to protect ports from contamination.
6. Thaw each infusion bag one at a time at 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Remove bag from thawing device immediately; do not store product bag at 37°C. Once the infusion bag has been thawed and is at room temperature (20°C to 25°C), it should be infused within 30 minutes. Do not wash, spin down, and/or resuspend KYMRIAH in new media prior to infusion.
7. Inspect the contents of the thawed infusion bag for any visible cell clumps. If visible cell clumps remain, gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not infuse KYMRIAH if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be compromised. Call Novartis at 1-844-4KYMRIAH.
Administration
8. Confirm the patient’s identity with the patient identifiers on the infusion bag.
9. Administer KYMRIAH as an intravenous infusion at 10 mL to 20 mL per minute, adjusted as appropriate for smaller children and smaller volumes. The volume in the infusion bag ranges from 10 mL to 50 mL. Do NOT use a leukocyte-depleting filter. If more than one bag is being infused for the treatment dose, wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered.
- Prime the tubing prior to infusion with sodium chloride 9 mg/mL (0.9%) solution for injection.
- Infuse all contents of the infusion bag.
- Rinse the infusion bag with 10 mL to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection while maintaining a closed tubing system to assure as many cells as possible are infused into the patient.
- Cells from all the bag(s) must be infused to complete a single dose.
KYMRIAH contains human cells genetically modified with a lentivirus. Follow local biosafety guidelines applicable for handling and disposal of such products.
Monitoring
- Administer KYMRIAH at a REMS-certified healthcare facility.
- Monitor patients 2-3 times during the first week following KYMRIAH infusion at the certified healthcare facility for signs and symptoms of CRS and neurologic toxicities [see Warnings and Precautions (5.1, 5.2)].
- Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion.
- Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.
Management of Severe Adverse Reactions
Cytokine Release Syndrome
Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1 (Lee et al., 2014). Alternative CRS management strategies may be implemented based on appropriate institutional or academic guidelines.
| aLee et al., 2014. bSantomasso et al., 2021. cRefer to tocilizumab Prescribing Information for details. dAlternative therapy includes anti-cytokine and anti-T cell therapies as per institutional policy and published guidelines such as (but not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, and ATG. | |||
| CRS grade a | Symptomatic treatment | Tocilizumab | Corticosteroids |
| Grade 1 Mild symptoms requiring symptomatic treatment only (e.g., low grade fever, fatigue, anorexia, etc.) | Exclude other causes (e.g., infection) and treat specific symptoms (e.g., with antipyretics, antiemetics, analgesics, etc.) | In patients with persistent (> 3 days) or refractory fever, consider managing as Grade 2 CRSb. | Not applicable |
| Grade 2 Symptoms require and respond to moderate intervention Oxygen requirement < 40% or Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity | Antipyretics, oxygen, intravenous fluids and/or low dose vasopressors as needed. | Administer tocilizumabc intravenously over 1 hour: - 8 mg/kg (max. 800 mg) if body weight ≥ 30 kg - 12 mg/kg if body weight < 30 kg If no improvement after first dose, repeat every 8 hours (limit to a maximum of 3 dosages in 24-hour period; maximum total of 4 doses). | If no improvement within 24 hours of tocilizumab, administer a daily dose of 2 mg/kg/day methylprednisolone intravenously (or equivalent) until vasopressor and oxygen no longer needed, then taper. If not improving, manage as appropriate grade below. |
| Grade 3 Symptoms require and respond to aggressive intervention Oxygen requirement ≥ 40% or Hypotension requiring high dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis | High-flow oxygen Intravenous fluids, and high-dose or multiple vasopressors Treat other organ toxicities as per local guidelines. | Per Grade 2 If not improving, consider alternative therapyd. | Per Grade 2 If not improving, manage as Grade 4. |
| Grade 4 Life-threatening symptoms Requirement for ventilator support or Grade 4 organ toxicity (excluding transaminitis) | Mechanical ventilation Intravenous fluids and high-dose vasopressor(s) Treat other organ toxicities as per local guidelines. | Per Grade 2 If not improving, consider alternative therapyd. | Administer methylprednisolone 1,000 mg intravenously one to two times per day for 3 days. If not improving, consider methylprednisolone 1,000 mg intravenously two to three times a day or alternate therapyd. Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate. |
Neurologic Toxicities
Patients should be monitored for neurologic toxicities, including ICANS, following KYMRIAH infusion, particularly during and after resolution of CRS. Identify neurologic toxicities based on clinical presentation. Evaluate for and treat other causes of neurological symptoms. Consider non-sedating seizure prophylaxis (e.g., levetiracetam) for patients at higher risk of seizure, such as those with seizure history, CNS disease, concerning EEG findings, or neoplastic brain lesions. If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Alternative neurologic toxicities management strategies may be implemented based on appropriate institutional, academic, or consensus guidelines.
| aASTCT criteria for grading NT (Lee et al., 2019); NCI CTCAE criteria for grading NT used in clinical trials. bICE Assessment Tool: (1) Orientation: orientation to year, month, city, and hospital: 4 points. (2) Naming: ability to name three objects (e.g., point to clock, pen, and button): 3 points. (3) Following commands: ability to follow simple commands (e.g., show me 2 fingers or close your eyes and stick out your tongue): 1 point. (4) Writing: ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point. (5) Attention: ability to count backward from 100 by 10: 1 point. cSantomasso et. al., 2021. dAlternate therapy may include anakinra, siltuximab, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone (50 mg) plus methotrexate (12 mg). *A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as Grade 4 ICANS if unarousable. | ||
| ICANS gradea | No concurrent CRS | Concurrent CRS |
| Grade 1 ICE scoreb: 7-9 with no depressed level of consciousness | Offer supportive care with intravenous hydration and aspiration precautions. | Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. Caution with repeated tocilizumab doses in patients with ICANS. Consider adding corticosteroids to tocilizumab past the first dosec. |
| Grade 2 ICE scoreb: 3-6 and/or Mild somnolence awaking to voice | Supportive care as above. Consider dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours) until the event is Grade 1 or less. If improving, taper corticosteroids. | Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. If refractory to tocilizumab past the first dose, administer dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours) until the event is Grade 1 or less, then taper corticosteroids. |
| Grade 3 ICE scoreb: 0-2* and/or Depressed level of consciousness awakening only to tactile stimulus and/or Any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or Focal or local edema on neuroimaging | Administer dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours). | Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. Administer dexamethasone 10 mg intravenously every 6-12 hours or methylprednisolone equivalent (1 mg/kg intravenously every 12 hours). Continue corticosteroids until the event is Grade 1 or less, then taper corticosteroids. If not improving, manage as Grade 4. |
| Grade 4 ICE scoreb: 0* (patient is unarousable and unable to perform ICE) and/or Stupor or coma and/or Life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or Diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing’s triad | Consider mechanical ventilation for airway protection. Administer high-dose methylprednisolone intravenously 1,000 mg one to two times per day for 3 days. If not improving, consider 1,000 mg of methylprednisolone two to three times per day or alternate therapyd. Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines. | Administer tocilizumab at any grade CRS, as per dosage recommendation in Table 1. Administer methylprednisolone 1,000 mg intravenously one to two times per day for 3 days. If not improving, consider methylprednisolone 1,000 mg intravenously two to three times per day or alternate therapyd. Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines. |
Pediatric and Young Adult r/r B-cell ALL (up to 25 years of age): A single dose of KYMRIAH contains 0.2 to 5.0 x 106 CAR-positive viable T cells per kg of body weight for patients 50 kg and below or 0.1 to 2.5 x 108 CAR-positive viable T cells for patients above 50 kg, suspended in one to three patient-specific infusion bag(s) [see How Supplied/Storage and Handling (16)].
Adult r/r DLBCL and r/r FL: A single dose of KYMRIAH contains 0.6 to 6.0 x 108 CAR-positive viable T cells, which may be suspended in one to three patient-specific infusion bag(s) [see How Supplied/Storage and Handling (16)].
See the CoA for actual cell count. The volume in the infusion bag ranges from 10 mL to 50 mL.
Pregnancy
Risk Summary
There are no available data with KYMRIAH use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with KYMRIAH to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if KYMRIAH has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, KYMRIAH is not recommended for women who are pregnant, and pregnancy after KYMRIAH administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Lactation
Risk Summary
There is no information regarding the presence of KYMRIAH in human milk, the effect on the breastfed infant, and the effects on milk production. A risk to the breastfed infant cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KYMRIAH and any potential adverse effects on the breastfed infant from KYMRIAH or from the underlying maternal condition.
Females and Males of Reproductive Potential
Pregnancy Testing
Pregnancy status of females with reproductive potential should be verified. Sexually-active females of reproductive potential should have a pregnancy test prior to starting treatment with KYMRIAH.
Contraception
See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with KYMRIAH.
Infertility
There are no data on the effect of KYMRIAH on male and female fertility.
Pediatric Use
The safety and efficacy of KYMRIAH have been established in pediatric patients with r/r B-cell ALL. Use of KYMRIAH is supported by a single-arm trial [see Clinical Studies (14.1)] that included 61 pediatric patients with r/r B-cell precursor ALL in the following age groups: 40 children (ages 2 years to less than 12 years) and 21 adolescents (ages 12 years to less than 17 years). No differences in efficacy or safety were observed between the different age subgroups or in comparison to the young adults in the trial.
The safety and efficacy of KYMRIAH in pediatric patients with r/r DLBCL and r/r FL have not been established.
Geriatric Use
The safety and effectiveness of KYMRIAH have not been established in geriatric patients with r/r B-cell ALL. Clinical studies of KYMRIAH did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
None.